Synaptic Regulation of Proopiomelanocortin Neurons Can Occur Distal to the Arcuate Nucleus

Abstract

Energy homeostasis is controlled to a large extent by various signals that are integrated in the hypothalamus. It is generally considered that neurons in each of the hypothalamic nuclei are regulated by afferent projections that terminate within the cell body region of the nucleus. However, here it is shown that hypothalamic proopiomelanocortin (POMC) neurons receive synaptic inputs onto distal dendrites that reside outside of the cell body region in the arcuate nucleus. Previous studies using whole cell recordings from identified neurons in brain slices have shown that cannabinoids reduce GABA release from inhibitory synapses onto the POMC cells. Here it was found that endocannabinoids inhibited GABAergic inhibitory postsynaptic currents in POMC neurons only in intact sagittal brain slices, but not coronal, horizontal, or sagittal slices that were truncated rostrally at the level of the optic chiasm. Thus endocannabinoids inhibited presynaptic GABA release only at an anatomically distinct subset of POMC-neuron dendrites that extends rostrally beyond the arcuate nucleus into preoptic hypothalamic regions. There are two key results. First, the activity of POMC neurons can be regulated by afferent input at sites much farther from the soma than previously recognized. Second, endocannabinoids can act to inhibit inputs only at selective dendrites. POMC neurons play a critical role in the maintenance of body weight. Therefore these data suggest that energy balance may be regulated, in part, by modulation of POMC neuron activity at sites outside of the arcuate nucleus. I N T R O D U C T I O NThe majority of proopiomelanocortin (POMC) neurons reside in the arcuate nucleus of the hypothalamus where they are well poised to carry out their roles in mediating homeostatic functions as they integrate signals from, and send projections to, the various hypothalamic nuclei and extrahypothalamic sites (Cone 2005). POMC neurons have received much attention recently because of their essential role in the maintenance of normal energy balance. This is clearly evidenced by the fact that the loss of POMC neurons or their peptide products results in increased body weight and obesity (Farooqi and O'Rahilly 2004;Gropp et al. 2005;Luquet et al. 2005;Smart and Low 2003;Smart et al. 2006;Yaswen et al. 1999). Accordingly, activation of POMC neurons correlates with decreased food intake. Determining how POMC neuron activity is regulated is of particular interest as such knowledge could help elucidate targets for the therapeutic treatment of obesity.To date, studies examining factors that regulate POMC neuron activity have primarily focused on peptides and rapid neurotransmitters released from terminals in the region of the POMC cell bodies. However, afferent inputs that terminate on dendrites can also play an important role in regulating neuronal activity. In POMC neurons, the anatomical distribution of dendrites has not been well characterized nor has the extent to which POMC neuron dendrites can extend beyond the soma. It has been difficult ...

Somato-Dendritic Localization and Signaling by Leptin Receptors in Hypothalamic POMC and AgRP Neurons

“…In randomly selected pSTAT3 IR (POMC) dendritic structures in brains of Lepr db/db ; Pomc-cre;HA-Leprb flox mice we did not find direct evidence of spines by EM. This is consistent with earlier reports by Hentges et al [59] and Liu et al [16] showing a low number of dendritic spines on POMC neurons. By CLSM, which allows rapid analysis of much larger fields and longer fiber distances, we did however observe pSTAT3 IR within rare spine-like structures on POMC dendrites (Figure S9).…”

Hypothalamic POMC neurons promote cannabinoid-induced feeding

“…We found that without TTX, low doses of ACEA (200 nM) induced depolarization of POMC neurons (Fig. 1d 2 ), as reported earlier 12 , while high doses of ACEA (1 µM) resulted in hyperpolarization of POMC cells (Fig. 1d 3 ).…”

Estrogen rapidly attenuates cannabinoid-induced changes in energy homeostasis

“…However, in these mice GABAergic but not glutamatergic synaptic input is tonically inhibited by endogenous cannabinoids acting on the distal dendrites of POMC neurons, as evidenced by the ability of CB 1 receptor antagonists to increase mIPSC frequency (Hentges et. al., 2005;Hentges, 2007;Sinnayah et. al., 2008).…”